The lack of human pluripotential bone marrow stem cell line has been a major deterrent to the study of stem cell differentiation. The K-562 leukemia cell line, originally established by us, has been characterized as a progenitor of the granulocytic series with an arrest of differentiation. The results of studies in progress indicate that K-562 blasts are multipotential leukemia cells that can undergo either spontaneous or induce differentiation along the erythrocytic, granulocytic, monocytic, lymphocytic, and (probably) into the megakaryocytic series. The specific aims are: (1) to study the potential for differentiation of cloned K-562 blasts into the five bone marrow cell series. By means of in vitro assays, we will study the event leading to differentiation of K-562 blasts into progenitors, precursors, and mature blood cells. The procedures followed will employ biological response modifiers and inducers of differentiation (differones) such as hemin, hematin, dimethylsulfoxide, retinoids, antigens, chloroquine, interferon,, thymus factors and thymic hormones, Interleukins-1 and 2, and specific antibodies including monoclonal antibodies to K-562 cells. (2) to assess if the K-562 cells lose their characteristic malignancy at some stage of differentiation and maturation. (3) to evaluate if the near triploid karyotype with a P[h 1+ chromosome and the translocation t(15;17) characteristic of K-562 blasts is modified during differentiation and maturation; (4) to determine if differentiated K-562 cells without the specific chromosome markers still proliferate in vitro; (5) to find out if K-562 cells have a change in leukemia-associated antigen expression during differentiation; (6) to explore whether an alteration of antigenic determinants also involve natural killer cells; and (7) to study the resistance (if any) of K-562 leukemia cells to lipid peroxidation, a phenomenon observed in most neoplastic cells but not in normal cells. The proposed studies require expertise in tissue culture, cytogenetics, hematology, oncology, pathology, and immunology. The results of the project may provide new knowledge on new therapeutic modalities of myelogenous, lymphatic and other types of human leukemia. It is theoretically possible that differones may not kill leukemia cells but will actually cause further irreversible differentiation into functional benign blood cells.